Kristin Hatten (top right), therapist, helps Grace Wilsey (bottom right), 4, prepare to mount Sebastian (left) as they wait on a mounting block at the National Center for Equine Facilitated Therapy on Friday, April 4, 2014, in Woodside, Calif. Wilsey has a N-glycanase deficiency disorder. less

Kristin Hatten (top right), therapist, helps Grace Wilsey (bottom right), 4, prepare to mount Sebastian (left) as they wait on a mounting block at the National Center for Equine Facilitated Therapy on Friday, ... more

Grace Wilsey (lower left), 4, plays with a toy kitchen with Matt Wilsey (top left), her father, after her equine therapy session as her mother Kristen Wilsey (second from right) talks with her therapist Kristin Hatten (right) at the National Center for Equine Facilitated Therapy on Friday, April 4, 2014, in Woodside, Calif. Wilsey has a N-glycanase deficiency disorder. less

Grace Wilsey (lower left), 4, plays with a toy kitchen with Matt Wilsey (top left), her father, after her equine therapy session as her mother Kristen Wilsey (second from right) talks with her therapist Kristin ... more

Grace Wilsey (atop horse), 4, waves to her parents Kristen Wilsey (left) and Matt Wilsey (second from left) during an equine therapy session with therapist Kristin Hatten (center foreground) therapist, at the National Center for Equine Facilitated Therapy on Friday, April 4, 2014, in Woodside, Calif. Wilsey has a N-glycanase deficiency disorder. less

Grace Wilsey (second from left), 4, races toward a play kitchen as she holds the hand of Matt Wilsey (second from right), her father, followed by her mother Kristen Wilsey (left) and Kristin Hatten (right), therapist, after an equine therapy session at the National Center for Equine Facilitated Therapy on Friday, April 4, 2014, in Woodside, Calif. Wilsey has a N-glycanase deficiency disorder. less

Grace Wilsey (second from left), 4, races toward a play kitchen as she holds the hand of Matt Wilsey (second from right), her father, followed by her mother Kristen Wilsey (left) and Kristin Hatten (right), ... more

In February 2013, Stanford geneticist Gregory Enns called the Wilsey family with news: He was "99 percent sure" that doctors had found the cause of their 3-year-old daughter's terrible congenital disease.

"That was a huge relief," said Kristen Wilsey, whose daughter, Grace, is now 4. "Other people may not understand how it can be such a relief to be told that your daughter has a very rare genetic disease for which there is no cure or treatment. But when you don't know what you're fighting, you have no direction. It meant we could start moving forward."

Grace is a patient in a research paper published last month about the newly discovered disease, called "NGLY1 deficiency" for now; the gene mutation that all the patients share is in the NGLY1 gene. Eight patients have been confirmed with the disorder so far, but doctors believe they've found at least another half dozen who haven't yet been formally diagnosed.

The Wilseys' journey toward diagnosis is demonstrative of what scientists hope is a new era of medicine, in which DNA testing can solve medical mysteries that once were unassailable.

It's also indicative of the power of teamwork, researchers say, and what can be accomplished when doctors and scientists make public an investigation - and invite families and patients into the fold.

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Something wrong

Grace was born by emergency cesarean section in October 2009. It had been a difficult pregnancy, and doctors noticed potential problems shortly after birth - Grace was lethargic, and her eyes were cloudy and gray. Within a day, she was having trouble feeding.

She also had elevated levels of a liver enzyme that suggested infection, so she was treated with antivirals and antibiotics. She stayed in the neonatal intensive care unit at Stanford for three weeks. Over the next several months at home she seemed to stabilize, but she fell behind on developmental milestones. By about 18 months, Grace had developed a tremor-like movement disorder. Her liver enzyme tests continued to cause concern.

And her parents noticed that when Grace cried, she rarely produced tears.

Doctors were perplexed.

"She had a constellation of symptoms that made you scratch your head," Enns said. "Developmental disease and liver disease and unusual movements and an inability to make tears - that was really an unusual combination."

Since the symptoms seemed indicative of a systemic problem - something that interfered with basic biological function - doctors believed it was caused by a genetic defect.

New diagnostic tools

Around this time, in spring 2011, whole genome and exome sequencing was beginning to gain traction as a diagnostic tool. Whole genome sequencing involves mapping a person's entire genetic code; whole exome sequencing looks at a small but critically important section of the code.

Whole genome sequencing was first done about a decade ago, but it's become a diagnostic tool only in the past couple of years. Even two or three years ago, it was unusual to perform such sequencing on a patient outside of a research study.

"Grace is probably one of the most sequenced living patients today," said Matt Wilsey.

Help on the Internet

Eventually the geneticists at Stanford and Baylor came up with a list of eight genetic mutations that they thought were most likely to be responsible for Grace's illness.

NGLY1 was at the bottom of the list.

And that's where the wonders of the World Wide Web come in to play. At the same time the Wilseys were hunting down Grace's genetic nemesis, so too were Matthew and Kristen Might of Salt Lake City. Their son, Bertrand, was born in December 2007 with a mysterious illness that made no sense to doctors.

The Mights had started writing a blog about their medical journey with Bertrand. They documented his symptoms, his meetings with doctors, the various theories bandied about. And they wrote up the results of his genetic sequencing at Duke University.

Making a connection

The Duke geneticists latched onto NGLY1 as a possible culprit. The gene is responsible for producing an enzyme, called N-glycanase 1, that helps break down damaged proteins at the cellular level. Bertrand, doctors discovered, was indeed lacking that enzyme.

Like the Wilseys, the Mights were excited about the diagnosis.

"It's a strange moment to be thrilled when your son has a terrible disease," Matthew Might said. "But we already knew he had a terrible disease - to start to think about ways to treat and cure this, in many ways it was a huge relief."

But to keep moving forward in understanding their son's disease, the Mights needed more evidence - specifically, they needed more patients like Bertrand. Matthew Might wrote up an essay on the family's diagnostic odyssey and had it published on a few well-trafficked websites. Meanwhile, Bertrand's doctors at Duke wrote up his case as an example of the powers of genetic sequencing.

And that's how things came back around to the Wilseys. At Baylor, geneticist Matthew Bainbridge had decided to look for further information on NGLY1 as a source of Grace's disease, and he found his answers in two unlikely places: Matthew Might's blog and Wikipedia.

"I feel silly saying it," Bainbridge said about the online encyclopedia. He doesn't typically use Wikipedia for research, but in this case, as he was skimming for basic information on NGLY1, he found a link to the Duke paper.

"I wrote to the Wilseys and asked, 'Does Grace make tears?' " Bainbridge said. The Wilseys confirmed that no, she rarely did. "That was the 'eureka' moment. That was 'bingo!' "

Unusual alliances

The doctors at Stanford performed tests to show that Grace was missing the N-glycanase 1 enzyme. Around the same time, other patients had started to come forward - either they had found Matthew Might's blog on their own or their doctors had seen it.

Before long, the doctors from Stanford, Duke and Baylor - by now, in fairly regular communication with one another - had collected eight cases, all confirmed to share the NGLY1 mutation. And the Mights and the Wilseys had started pulling patient families together; Matthew Might runs an e-mail list with a dozen or so families so far.

Family involvement - specifically, the work done by the Mights and the Wilseys - was critical to solving the NGLY1 mystery, scientists say. But the irony is that just a few years ago, inviting that kind of involvement would have been unfathomable.

Even the kind of collaboration that happened among scientists at different - arguably competitive - institutions was remarkable, said Hudson Freeze, director of the Human Genetics Program at the Sanford Burnham Medical Research Institute in La Jolla. Freeze is a glycobiologist who has been consulting with the NGLY1 families.

"We're on the cusp of revolutionizing the way this kind of research is done," Freeze said. "NGLY1 should be held up as an example of how patients and families and physicians and bloggers can all work together."

Fathers write essay

For the Mights and the Wilseys, along with the other families with NGLY1 children, just finding each other already has proved invaluable, they say. They can better understand their children's symptoms and have more clues as to what to expect - at least two of the patients identified so far have survived past their late teens, which is reassuring information for parents who had no idea how long their children might live.

And the families are helping propel efforts to start a clinical trial to test a drug that might counteract the effects of the NGLY1 mutation and help children produce the enzyme they're missing.

Alongside the research paper published by scientists last month, Matthew Might and Matt Wilsey wrote their own essay - a plea, of sorts, to continue the collaboration between patients and families and researchers.

"The capabilities of parents and the social media are frequently underestimated," the men wrote in the essay, published in the journal Genetics in Medicine. "We are here to say: 'Join us!' "

"We really want to change the way diseases are discovered, researched and ultimately treated," Matt Wilsey said in an interview. "That's a pretty monumental task for a couple of guys who have no degrees in medicine. But a good idea can come from anywhere."

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